Vladimir Matchkov

Involvement of transglutaminase 2 and voltage-gated potassium channels in cystamine vasodilatation in rat mesenteric small arteries

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Involvement of transglutaminase 2 and voltage-gated potassium channels in cystamine vasodilatation in rat mesenteric small arteries. / Engholm, Morten; Pinilla, Estéfano; Mogensen, Susie; Matchkov, Vladimir; Hedegaard, Elise Røge; Chen, Hua; Mulvany, Michael J; Simonsen, Ulf.

In: British Journal of Pharmacology, Vol. 173, No. 5, 01.03.2016, p. 839-855.

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@article{133c2f61e09b4b569b7f87d2b3388004,
title = "Involvement of transglutaminase 2 and voltage-gated potassium channels in cystamine vasodilatation in rat mesenteric small arteries",
abstract = "BACKGROUND AND PURPOSE: Vasodilatation may contribute to the neuroprotective and vascular antiremodelling effect of the tissue transglutaminase (TG2) inhibitor cystamine. The present study hypothesized that inhibition of TG2 followed by blockade of smooth muscle calcium entry and/or inhibition of Rho kinase underlie cystamine vasodilatation.EXPERIMENTAL APPROACH: In rat mesenteric small arteries: RT-PCR, immunoblotting, and measurements of isometric wall tension, intracellular Ca(2+) ([Ca(2+) ]i ) , K(+) currents (patch clamp), and phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and myosin regulatory light chain (MLC2).KEY RESULTS: RT-PCR and immunoblotting revealed expression of TG2 in mesenteric small arteries. Cystamine concentration-dependently inhibited curves for phenylephrine, 5-hydroxytryptamine, U46619, and for extracellular K(+) . Selective inhibitors of TG2, LDN 27129 and T101, also inhibited phenylephrine contraction. An inhibitor of phospholipase C suppressed cystamine relaxation. Cystamine relaxed and reduced [Ca(2+) ]i in phenylephrine-contracted arteries. In potassium-contracted arteries, cystamine induced less relaxation without changing [Ca(2+) ]i , and these relaxations were blocked by mitochondrial complex inhibitors. Blockers of voltage-gated potassium KV 7 channels, XE991 and linopirdine inhibited cystamine relaxation and increases in voltage-dependent smooth muscle currents. Cystamine and the Rho kinase inhibitor Y27632 reduced basal MYPT1-Thr(855) phosphorylation, but only Y27632 reduced phenylephrine-induced increases in MYPT1-Thr(855) and MLC2 phosphorylation.CONCLUSIONS AND IMPLICATIONS: Our findings suggest that cystamine induces vasodilatation by inhibition of receptor-coupled TG2 leading to opening of KV channels and reduction of intracellular calcium, and by activation of a pathway sensitive to inhibitors of the mitochondrial complexes I and III. Both pathways may contribute to the antihypertensive and neuroprotective effect of cystamine.",
author = "Morten Engholm and Est{\'e}fano Pinilla and Susie Mogensen and Vladimir Matchkov and Hedegaard, {Elise R{\o}ge} and Hua Chen and Mulvany, {Michael J} and Ulf Simonsen",
note = "This article is protected by copyright. All rights reserved.",
year = "2016",
month = mar,
day = "1",
doi = "10.1111/bph.13393",
language = "English",
volume = "173",
pages = "839--855",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "John/Wiley & Sons Ltd.",
number = "5",

}

RIS

TY - JOUR

T1 - Involvement of transglutaminase 2 and voltage-gated potassium channels in cystamine vasodilatation in rat mesenteric small arteries

AU - Engholm, Morten

AU - Pinilla, Estéfano

AU - Mogensen, Susie

AU - Matchkov, Vladimir

AU - Hedegaard, Elise Røge

AU - Chen, Hua

AU - Mulvany, Michael J

AU - Simonsen, Ulf

N1 - This article is protected by copyright. All rights reserved.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - BACKGROUND AND PURPOSE: Vasodilatation may contribute to the neuroprotective and vascular antiremodelling effect of the tissue transglutaminase (TG2) inhibitor cystamine. The present study hypothesized that inhibition of TG2 followed by blockade of smooth muscle calcium entry and/or inhibition of Rho kinase underlie cystamine vasodilatation.EXPERIMENTAL APPROACH: In rat mesenteric small arteries: RT-PCR, immunoblotting, and measurements of isometric wall tension, intracellular Ca(2+) ([Ca(2+) ]i ) , K(+) currents (patch clamp), and phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and myosin regulatory light chain (MLC2).KEY RESULTS: RT-PCR and immunoblotting revealed expression of TG2 in mesenteric small arteries. Cystamine concentration-dependently inhibited curves for phenylephrine, 5-hydroxytryptamine, U46619, and for extracellular K(+) . Selective inhibitors of TG2, LDN 27129 and T101, also inhibited phenylephrine contraction. An inhibitor of phospholipase C suppressed cystamine relaxation. Cystamine relaxed and reduced [Ca(2+) ]i in phenylephrine-contracted arteries. In potassium-contracted arteries, cystamine induced less relaxation without changing [Ca(2+) ]i , and these relaxations were blocked by mitochondrial complex inhibitors. Blockers of voltage-gated potassium KV 7 channels, XE991 and linopirdine inhibited cystamine relaxation and increases in voltage-dependent smooth muscle currents. Cystamine and the Rho kinase inhibitor Y27632 reduced basal MYPT1-Thr(855) phosphorylation, but only Y27632 reduced phenylephrine-induced increases in MYPT1-Thr(855) and MLC2 phosphorylation.CONCLUSIONS AND IMPLICATIONS: Our findings suggest that cystamine induces vasodilatation by inhibition of receptor-coupled TG2 leading to opening of KV channels and reduction of intracellular calcium, and by activation of a pathway sensitive to inhibitors of the mitochondrial complexes I and III. Both pathways may contribute to the antihypertensive and neuroprotective effect of cystamine.

AB - BACKGROUND AND PURPOSE: Vasodilatation may contribute to the neuroprotective and vascular antiremodelling effect of the tissue transglutaminase (TG2) inhibitor cystamine. The present study hypothesized that inhibition of TG2 followed by blockade of smooth muscle calcium entry and/or inhibition of Rho kinase underlie cystamine vasodilatation.EXPERIMENTAL APPROACH: In rat mesenteric small arteries: RT-PCR, immunoblotting, and measurements of isometric wall tension, intracellular Ca(2+) ([Ca(2+) ]i ) , K(+) currents (patch clamp), and phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and myosin regulatory light chain (MLC2).KEY RESULTS: RT-PCR and immunoblotting revealed expression of TG2 in mesenteric small arteries. Cystamine concentration-dependently inhibited curves for phenylephrine, 5-hydroxytryptamine, U46619, and for extracellular K(+) . Selective inhibitors of TG2, LDN 27129 and T101, also inhibited phenylephrine contraction. An inhibitor of phospholipase C suppressed cystamine relaxation. Cystamine relaxed and reduced [Ca(2+) ]i in phenylephrine-contracted arteries. In potassium-contracted arteries, cystamine induced less relaxation without changing [Ca(2+) ]i , and these relaxations were blocked by mitochondrial complex inhibitors. Blockers of voltage-gated potassium KV 7 channels, XE991 and linopirdine inhibited cystamine relaxation and increases in voltage-dependent smooth muscle currents. Cystamine and the Rho kinase inhibitor Y27632 reduced basal MYPT1-Thr(855) phosphorylation, but only Y27632 reduced phenylephrine-induced increases in MYPT1-Thr(855) and MLC2 phosphorylation.CONCLUSIONS AND IMPLICATIONS: Our findings suggest that cystamine induces vasodilatation by inhibition of receptor-coupled TG2 leading to opening of KV channels and reduction of intracellular calcium, and by activation of a pathway sensitive to inhibitors of the mitochondrial complexes I and III. Both pathways may contribute to the antihypertensive and neuroprotective effect of cystamine.

U2 - 10.1111/bph.13393

DO - 10.1111/bph.13393

M3 - Journal article

C2 - 26603619

VL - 173

SP - 839

EP - 855

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 5

ER -